The American Society for Microbiology (ASM) appreciates the opportunity to provide comments on the Food and Drug Administration’s Reclassification of Influenza Virus Antigen Detection Test Systems Intended for Use Directly with Clinical Specimens as published in the Federal Register of 22 May, Docket No. [FDA–2014–N–0440].

The ASM is the largest single life science society, with over 39,000 members. Its members work in educational, research, industrial, and government settings on issues such as the environment, the prevention and treatment of infectious diseases, laboratory and diagnostic medicine, and food and water safety. Many of ASM’s members have primary involvement in clinical laboratory medicine including individuals directing clinical microbiology, immunology and molecular diagnostic laboratories, individuals licensed or accredited to perform such testing, industry representatives developing laboratory products for use, and researchers involved in the evaluation of new technologies.

The rapid and documented emergence of novel or variant influenza strains requires a more stringent oversight of rapid influenza direct tests (RIDTs) to ensure the accuracy and safety of their use. This need has been clearly demonstrated by the poor performance of some RIDTs, particularly with newly emerging strains of influenza, such as the 2009 influenza A pandemic strain. Under pandemic testing conditions, studies by numerous investigators and by the U. S. Centers for Disease Control and Prevention (CDC) demonstrated that the sensitivities of RIDTs ranged from as low as 20% to 80% and specificities ranged from approximately 50% to 95% (1-3). Although newer RIDTs are designed to better detect the currently circulating influenza strains, these strains can undergo antigenic drift over time. Additionally, at any time, we may again be faced with a new pandemic variant with very different antigenic properties, which may adversely affect the performance of even the newly developed RIDTs.

Poor analytical and clinical performance of RIDTs can have a significant clinical impact on patient outcome and a financial impact on laboratory services and utilization of health care resources. Tests with poor sensitivities and specificities, leading to both false negative and false positive results, can cause missed diagnoses due to the presence of multiple co-circulating respiratory viruses and the significant overlap in clinical presentation they may have. An incorrect diagnosis can affect treatment selection, who should receive an anti-viral and/or antibiotic therapy, increase the risk of nosocomial spread due to a lack of appropriate infection control practices, or conversely, initiate costly infection control practices that are unnecessary. Laboratories must often reflex samples with negative RIDT results to more sensitive methodologies such as viral culture and molecular methods, with a significant increase in testing costs and a delay in time to results.

Clinicians and laboratorians must be aware of the clinical performance of their RIDTs when interpreting the test results. One must keep in mind that package insert data is obtained using strict clinical trial procedures and oversight, using optimal sample types, time of sample collection post onset of symptoms, proper sample storage and time to testing. These conditions are often not maintained in daily clinical use, thereby potentially reducing the actual performance of the assays in “real life” settings such as a busy emergency department, outreach clinic or physician’s office. Additionally, since RIDTs are currently listed as class I devices, there is no requirement for the manufacturer to regularly re-evaluate analytical performance in relation to circulating influenza strains once the device has received FDA clearance. Therefore, physicians and laboratorians must rely on clinical experience, data on local influenza activity, monitor reflex testing results to ascertain local test performance. Other useful information includes local, national and international surveillance data regarding the current circulating strains and the known limitations of the assays with newly emerging strains such as influenza A H5. However, a laboratory’s RIDT verification data, perhaps established years previously, may no longer be valid as strains drift over time; often in the community setting there is a lack of test knowledge and a general reliance on manufacturer’s package insert data. All of these factors can result in poor RIDT clinical performance that remains undetected for multiple influenza seasons.

The ASMbelieves that a critical component in assuring acceptable RIDT performance is the obligation of RIDT manufacturers to ensure the continued quality and performance of the assays with current influenza strains. Additionally, manufacturers should be obligated to take immediate action in re-evaluating their test when a new strain emerges. Therefore, the ASM fully supports the FDA’s proposal and the FDA’s Microbiology Advisory Panel recommendation from June 2013 that all RIDTs currently regulated under § 866.3330 be reclassified into class II with special controls under the new device name “influenza virus antigen detection test system.” Special controls that: (1) Identify the minimum acceptable performance criteria; (2) identify the appropriate comparator for establishing performance of new assays; and (3) call for mandatory annual analytical reactivity testing of contemporary influenza strains, including testing of newly emerging strains that pose a danger of public health emergency, would provide reasonable assurance of safety and effectiveness of RIDTs. The American Society for Microbiology is also in agreement that although the FDA may exempt a class II device from the premarket notification requirements under section 510(k), for this device, premarket notification is necessary to provide reasonable assurance of safety and effectiveness.